Age-related macular degeneration (AMD) is the leading cause of blindness in the U.S. and currently affects more than 15 million people (13.5 million dry-form & 1.6 million neovascular-form). Despite the epidemic of vision loss caused by AMD, only a few therapies can slow the progression of AMD and even fewer can reverse vision loss. Currently favored therapeutic modalities include Lucentis and off-label use of Avastin, both of which target a single growth factor VEGF, and appear to exert most of their beneficial effect via an anti-permeability action resulting in resolution of intra and sub-retinal edema, as the actual CNV lesion does not markedly involute. Exudative AMD-related vision loss however, is not due solely to CNV induced sub-retinal and intra-retinal edema. Pathologic disruption and remodeling of the retinal and subretinal architecture caused collectively by CNV, sub-retinal fibrosis, edema and inflammation results in the loss of visual acuity associated with AMD. These multiple causes of retinal injury are not addressed by available treatments. Agents having the ability to treat the multiple mechanisms which underlie exudative AMD-related vision loss, beyond just treating vascular leakage, would be of great value and are likely to fulfill the unmet medical need associated with exudative AMD. Lpath has recently developed Sonepcizumab, a novel humanized monoclonal antibody directed against the bioactive lysophospholipid, sphingosine-1-phosphate (S1P). Sonepcizumab represents the first successfully created monoclonal antibody against a lysophospholipid. Sonepcizumab acts as a molecular sponge to selectively and specifically with picomolar affinity, absorb S1P from the extracellular fluid, lowering the effective concentration of S1P. Growing evidence suggests that S1P could contribute to both the early and late stages of maladaptive retinal remodeling associated with exudative AMD. S1P has a pronounced non-VEGF dependent pro-angiogenic effect. S1P also stimulates migration, proliferation and survival of multiple cell types, including fibroblasts and endothelial and inflammatory cells that participate in the multiple maladaptive processes of exudative AMD. S1P is also linked to the production and activation of VEGF, FGF, PDGF MCP-1, IL-6, IL-8 and other growth factors implicated in the pathogenesis of exudative AMD. Inhibiting the action of S1P could therefore be an effective therapeutic treatment for exudative AMD that may offer significant advantages over exclusively anti-VEGF approaches or act synergistically with them to address the complex processes and multiple steps that ultimately lead to AMD associated visual loss. In Lpath's Phase I SBIR studies, the murine anti-S1P antibody demonstrated profound efficacy to reduce choroidal neovascularization as well as other vascular and extravascular processes of AMD in a murine model. In continuation of the R&D efforts initiated in Phase I, we hereby propose as series of Phase II studies to test whether neutralization of S1P with the humanized antibody, Sonepcizumab, is an effective strategy for the treatment of exudative AMD. The first goal of the Phase II research plan is to evaluate the pharmacological activity/efficacy of Sonepcizumab to reduce the multiple pathologies of exudative AMD in a laser-induced Cynomolgus monkey model of CNV. We will investigate the ability of Sonepcizumab to mitigate not only neovascularization and edema but also sub-retinal fibrosis and inflammation in comparison and synergistically with Lucentis, an anti-VEGF therapy. The second goal is to assess the safety of Sonepcizumab after repeat intravitreous administration to Cynomolgus monkeys. Finally, the mechanism of action by which Sonepcizumab is able to mitigate the multiple etiologies of AMD will be investigated. The successful completion of these Phase II studies will demonstrate the efficacy and safety profiles of Sonepcizumab to support an IND filing and subsequent clinical trials. Project Narrative Age-related macular degeneration (AMD) is the leading cause of blindness in the U.S. and currently affects more than 15 million people (13.5 million dry-form & 1.6 million neovascular-form). There are estimated to be 3 times this many cases worldwide. Despite the epidemic of vision loss caused by AMD, only a few therapies, mostly anti-VEGF based, can slow the progression of AMD and even fewer can reverse vision loss. Discovering new treatments for this form of pathologic neovascularization is therefore extremely important to society. [unreadable] [unreadable] [unreadable]